Granulomatous inflammation is a common disease mechanism. Few relevant experimental models exist for study of these reactions, although the Schistosome egg granuloma has provided useful information. We propose to study systematically granulomas induced by preformed complexes of antigen and antibody (see Spector and Heesom, J Path 98:31, 1969). Critical details of the reaction have not been pursued. We propose to use antigens that are particulate but not phagocytable, particulate and phagocytable, floccular, large and soluble, and small and soluble. The role of antibody will be studied by antibody class (e.g., IgM or IgG), or antibody fragments (e.g., F(ab)'2) in the induction of granulomatous reactions. Further, the orientation of antibody will be controlled with Fc portion either exposed or buried. The mechanism of mononuclear cell accumulation in early reactions will be studied in rabbits, guinea pigs and rodents and in their counterparts deficient in complement components C4, C5 or C6 or depleted of serum complement with cobra venom factor. The fate of antigen and antibody in mononuclear cells will be studied with radiolabeled antigen or antibody. Since earlier studies suggest monocytes (but not epithelioid cells or giant cells) retain but do not degrade antigen-antibody complexes prepared at equivalence, the mechanism whereby monocytes fail to degrade these complexes will be ascertained in vitro. The antigens, ferritin and peroxidase, will be selected to facilitate localization on or within cells. Such studies have relevance for human diseases such as sarcoidosis, infectious granulomas, granulomatous angiitis, or granulomas with "necrobiosis" or caseation.